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Cellular pathophysiology.

Part 2: responses following hypoxia
1 July, 2003
Sharon Edwards, MSc, RN, DipN, PGCEA. Senior Lecturer, Department of Nursing and Midwifery, University of Hertfordshire

During hypoxic injury blood flow falls below a certain critical level that is required to maintain cell viability. The interrupted supply of oxygenated blood to cells results in anaerobic metabolism and loss of adenosine triphosphate (ATP), and cellular membrane disruption (see Figure 1).

During hypoxic injury blood flow falls below a certain critical level that is required to maintain cell viability. The interrupted supply of oxygenated blood to cells results in anaerobic metabolism and loss of adenosine triphosphate (ATP), and cellular membrane disruption (see Figure 1). The nurse's role following injury or hypoxia to cells is related to maintaining a normal haemodynamic state, prevent excessive cellular/organ damage and loss of circulating volume. This involves the administration of oxygen, fluids and adequate nutrition. Pharmacological interventions may be available as treatment options for the future. Cellular changes Cellular changes can be caused by any of the types of injury listed in Table 1 in the first paper in this series (Edwards, 2003), including hypovolaemia/ hypotension, pressure sores, heart failure, myocardial infarction, shock and pulmonary embolism. All these states can, if left to progress, interfere with tissue perfusion, oxygen transport and the synthesis of ATP, leading to a reduction in the availability of energy, nutrients and ultimately hypoxia, causing serious cell damage. Cellular energy production Nutrients, such as glucose and fatty acids, as well as oxygen, enter the cell across the cell membrane. Hypoxic injury results in an inadequate flow of nutrients and oxygen to the cell. If tissue perfusion continues to be insufficient, hypoxia occurs and the cell resorts to anaerobic metabolic pathways for energy production. This produces several changes in cell function: mitochondrial activity is diminished due to a lack of oxygen for glycolysis and the electron transport chain; cellular ATP stores are rapidly used up (Gosling, 1999). The end product is lactic acid and nitric oxide, which can rapidly build up in high concentrations in the cell and blood, lowering the pH. The formation of lactic acid Consequently, the results of anaerobic metabolism are the production of lactic acid and a reduction in the energy available for cell work. Lactic acidosis reduces myocardial contractility, arteriolar responsiveness to further adrenaline and noradrenaline release, potentiating vasomotor collapse and stimulating the intravascular clotting mechanism. However, acidaemia has the beneficial effect of shifting the oxyhaemoglobin dissociation curve to the right, thereby facilitating the release of oxygen from haemoglobin (Marieb, 2001). Eventually, a large number of cytotoxic, vasodilator, vasoactive and other substances are released from the cell into the circulation, resulting in progressive

Nitric oxide can accumulate in high concentrations. driven by osmotic forces causing cellular swelling and distortion. electrons build up on carriers. 1992). This may affect the conduction of electrical impulses within the cells. The contraction of muscle results from the passage of electrical impulses down specialised pathways.vasodilatation. Anaerobic glycolysis leads to the accumulation of lactic acid. myocardial depression. increased capillary permeability and. The carriers are unable to pass on the electrons to the next level (Zuccarelli. one of the most rapid effects of hypoxia. 1999). which may interfere with organelle function (Buckman et al. 2000). with a rapid efflux of potassium from the cell. and movement of sodium and calcium into the cell (Gosling. Without intervention oxygen deprivation will be accompanied by cellular membrane disruption. causing cellular oedema and an increased intracellular osmotic pressure (Edwards. 2001). further stimulating the inflammatory response (Huddleston. 1997). Thus. leading to electrolyte disturbance. not simply due to direct cellular injury but also due to the systemic intracellular energy debt. The most well-known molecule associated with the formation of free radicals is nitric oxide. but their damaging presence usually results from an absence of oxygen. 2001). These may . The high intracellular potassium and low intracellular sodium and calcium concentration are maintained by active transport systems. intravascular coagulation (Huddleston. Without sufficient supplies of ATP the plasma membrane of the cell can no longer maintain normal ionic gradients across the cell membranes and the sodium potassium pump can no longer function. When oxygen is missing or diminished. which require the movement of sodium and potassium ions in and out of the cell to produce an action potential. Under normal circumstances this is a potent vasodilator and a regulator of blood flow (Marieb. which in normal physiology is the final resting place for electron flow via the mitochondrial electron transport chain. and a shortage of ATP. Increased sodium in the interior of cells result in water also entering the cell. eventually. Potassium leaks into the extracellular space and sodium followed by water will move into the cell. 1992). This changes the ionic concentration of potassium and sodium. The cytoplasmic membrane of cells becomes increasingly permeable to larger molecular weight proteins. The formation of free radicals/nitric oxide Free radicals can be formed in a number of ways. and a reduction in ATP for cellular work. there is a rapid shift from aerobic to anaerobic metabolism. 2000). The mitochrondria can lose their membrane potential in high concentrations of nitric oxide and halt ATP production all together. The cell may eventually burst. The end result of these mechanisms include those listed in Box 1 (Zuccarelli. 1992). This process can lead to endothelial damage. is perturbation of the normal ionic gradients across the cell membrane. and can react with other free radicals thereby setting up two mechanisms of cell death: oxidative injury and energy depletion (Edelstein et al. which require an intact cell membrane and functioning ionic channels. Cellular membrane disruption As oxygen levels fall in the cell.

and may be the hallmark of irreversible cellular injury and. its toxicity requires it to be sequestered and buffered when released. intracellular acidaemia becomes extreme. resulting in reversal of sodium/ calcium pumps and calcium is pumped in. Implications for practice The nursing interventions that relate to the physiological processes that occur following an injury or hypoxia are related to maintaining a normal haemodynamic state. resulting in self-digestion of the cell. 1992). Its paramount role requires calcium to be readily available to the cell stored in cellular organelles. causing structural derangement of the organelles. These changes are reversible if the oxygen is restored. cellular dysfunction becomes intemperate. Eventually the lysosomal membrane becomes more permeable and may rupture. calcium accumulates in the mitochondria. Oxygen supply and demand is maintained in balance as long as supplies of oxygen are available and carbon dioxide is eliminated through ventilation. . 2001). The role of lysosomes An important cell structure containing enzymes. This allows the release of lysosomal enzymes. Intracellular calcium is an important signalling system responsible for activation of phospholipases and proteases. 1982). diffusion and cell metabolism. preventing excessive cellular/ organ damage and loss of circulating volume. eventually. the lysosomal membrane becomes fragile when the cell is injured or deprived of oxygen (Marieb. allowing cells to contract normally. and its derangement results in membrane disruption and remodelling (Zuccarelli. 1999). It is critical in maintaining membrane potentials and in promoting the release of neurotransmitters at the synapse (Zuccarelli. Oxygen supply and demand/prevention of respiratory failure An imbalance between oxygen supply and tissue demands is fundamental to the nature of the insult. There is ample evidence to identify excess intracellular calcium as the true neurotoxic ion following hypoxia. perfusion. Any alteration of any part of these processes cause impaired gas exchange. The role of calcium The influx of calcium into the cell has a different cause than the initial membrane permeability change involving sodium and potassium. The use of steroids is thought to help stabilise the lysosomal membrane and prevent lysosmal enzyme damage to the cell (Guthrie. death (Buckman et al. This leads to intracellular lysosome membrane disruption and intracellular calcium and may finally lead to irreversible cell damage and death. The mechanisms by which the calcium content of cells is regulated are dysfunctional because of a lack of ATP (Gosling and Alpar. As a result. 2000). its passage controlled by a large variety of voltage-gated and ligand-gated channels (Tymianski and Tator. Physiological progression If left unchecked. which break down cell waste. 2000). The alteration in channel permeability results in depolarisation of the cell membrane. 1996). The importance of calcium cannot be underestimated. Lysosomal membrane instability is made worse by the lack of ATP and the cell starts to use its own structural phospholipids as a nutrient source.limit movement and contraction of muscle and tissues affected.

leading to a supply-demand deficit that gives rise to an oxygen debt. A patient with profound injuries will have hypermetabolism due to stress. and glycogen stores are converted via glycogenolysis. which causes tissue oedema in the area. function and result in a relative rather than true hypovolaemia (Edwards. elevated levels of liver enzymes. production of lactic acid and the lowering of blood pH. The nurse is responsible for administrating humidified oxygen. The administration of adequate nutrition With the stimulation of the neuroendocrine system there is a substantial increase in metabolic rate. colloid solution or a combination of all (Edwards. This can exhaust the patient. 2001). and hepatic encephalopathy . immune function and tissue repair all require an increase in nutritional substrates to support their function (Lehmann. Inflammation. The coagulation may cause blockage of the vasculature as a result of microvascular thrombi. and the regional circulation causing vasodilatation. 1998). When these processes become overwhelmed. In an acid environment chemoreceptors are stimulated. leading to increased demands for oxygen. 1998). and increased breakdown of fat (lipolysis). The vasodilatation in certain areas increases blood flow. organs. However. but these are not always available in all clinical situations. the movement of fluid from the circulation due to permeability changes. Energy requirements are amplified to supply nutrients and oxygen to active tissues and organs involved in the defence against the results of injury. There are detailed arterial blood gas tests that can be done to determine acid base balance. blood products. Therefore. and use mixed fuel sources. The release of catecholamines causes decreased deposition of fat stores (lipogenesis). including hyperbilirubinaemia. leading to signs and symptoms of liver failure. deficits in oxygen supply may exist when the lungs are not directly injured. This may require the use of blood. This amplification of energy production is accomplished at the expense of lean body mass. causing damage to the chest wall and pulmonary contusions. Prevention of a low circulating volume The release of mediators effects the microvasculature. permeability changes. a balanced salt and/or water solution. the victim is at risk of pulmonary complications. as any insult may give rise to an increase in demand over supply. The consequence of selective vasoconstriction and dilatation is a maldistribution of circulating volume and may lead to organ dysfunction (Huddleston. Amino acids and glycerol are converted into glucose via gluconeogenesis. The movement of fluid and vasodilatation impede cell movement. and coagulation. The result is a hyperglycaemia. depth and pattern of breathing and any signs of change. and consequently this increases respiratory rate in an attempt to eliminate the excess acid. the nurse's role is to administer prescribed fluid regimens for the immediate restoration of an effective circulating blood volume. the continuous frequent monitoring of respiratory rate. and the production of carbon dioxide and heat. oxygen consumption. and contributes to the disruption of the normal circulation (Edwards. All potential sources of glucose are mobilised as sources of fuel. 1993). 1992). leading to cellular hypoxia.Oxygen supply and demand deficits may relate to pulmonary trauma. The liver degrades fatty acids for use as fuel. which causes further tissue damage. and fat deposits may accumulate in the liver. due to the neuroendocrine response.

(Cheevers. their secretions. and interventions that maintain circulating volume. As protein continues to be broken down and used for energy serum. together with observing for signs of shock and deterioration. reducing their function. causing pooling of fluid in the interstitial space. The myocardium becomes depressed. chemical involvement and the complex activation of neurohormones released within minutes of the initial injury that are the true culprits in death and disability associated with certain conditions. Immediate pharmacological intervention aimed at deterring the onset or progress of cell death could define the future of emergency care (Zimmerman et al. Clearly protein depletion and starvation contribute to morbidity and mortality following an insult. There is an increase in cellular metabolism. magnesium and phosphate loss (Tan. rendering membrane potentials useless to maintain organ function. and hypoalbuminaemia. and the nervous system are highly regulated and serve to benefit human body functions. Therefore it is imperative to initiate feeding regimens early (Edwards. and the prevention of shock. depriving it of control over its micro-circulation and necessary oxygen. 2002). 1997). 1997). 1999). The interconnections between cellular elements. leading to dysfunction. levels of proteins reduce (Chee-vers. The nurse's role in caring for the patient with a hypoxic or cellular injury is mainly focused on maintaining haemodynamic abnormalities such as circulating volume. which is associated with impaired wound healing (Tan. They act together to choke the tissue. The timing and the route of nutritional support can favourably influence the metabolic response to injury. cardiac work and carbon dioxide production. A decreased level of these proteins. 2000). the immune system. Circulating proteins are responsible for maintaining stability of the colloidal oncotic pressure of the vascular bed. oxygen consumption. It is now being proposed that it is the cellular. characterised by oedema. It is now . When there is traumatic or hypoxic injury to cells. nutrition and oxygen levels. the interconnections between these systems becomes evident. administration of oxygen to meet supply and demand. Protein loss is accompanied by potassium. Pharmacological interventions Treatments for conditions such as heart failure. the effects of which can continue for months or years after the initial event (Edward. Zinc distributed via the liver becomes deficient. This type of nursing is demanding and intense. and deprives cells of nutrients. Conclusion The cellular elements and the chemical mediators which are released within minutes of an injury/ hypoxia do not act alone. trauma and so on. 1993). There are continued efforts to discover new drugs that could prove essential as our understanding of the epidemiology of disease develops. The use of all energy sources following an insult causes an exhaustion of energy stores and sources. result in decreased colloidal oncotic pressure. such as albumin. generally focus on haemodynamic abnormalities. Prevention of shock is discussed in Box 2. There has recently been a steady increase in research looking at the release of mediators following cell injury. 1999).

. when treating victims with any physiological insult there is a possibility of further injury and even death from events totally unrelated to the initial injury. Therefore. The fact that the mediators of injury are already resident in normal physiology means that their activity can be modified or pathways promoted that can lead to regeneration. There is hope for effective pharmacological intervention at the initial stages. before further injury begins. This is the direction of much current essential clinical research and could revolutionise the future of nursing care. which occur as the body tries to compensate for haemodynamic abnormalities.thought that the progressive worsening of some conditions results from neurohormonal changes.